Grey matter volume correlates of cerebrospinal markers of Alzheimer-pathology in Parkinson's disease and related dementia
Introduction
Dementia is frequent in Parkinson's disease (PD) [1] and there is growing evidence from both experimental [2] and clinico-pathological [3], [4] studies favouring the role of Alzheimer's disease (AD) pathology in PD-related dementia (PDD), probably as part of a synergistic model where α-synuclein, the protein primarily altered in PD, and amyloid β (Aβ) and τ, implicated in AD pathophysiology, would interact leading to an accelerated neurodegenerative process [2], [3], [4].
Currently, a number of cerebrospinal fluid (CSF) and PET biomarkers of AD are also being used to assess in vivo the presence of AD pathology in PD [5]. In terms of CSF, we have reported high CSF τ and phospho-τ levels (believed to reflect neuronal-axonal degeneration and neurofibrillary pathology) [6] in part of PDD patients and a gradation of CSF Aβ levels (believed to reflect senile plaques) [6], ranging from high concentrations in controls to low values in PDD, with non-demented PD (PDND) cases displaying intermediate levels [7]. Other studies have highlighted low CSF Aβ levels as a correlate of memory deficits in de novo untreated, non-demented PD patients [8], and as predictors of impending cognitive decline in PDND subjects [9]. Altogether, these studies suggest that an AD-like CSF signature can be present in PD-related cognitive decline and dementia, with information on PET imaging of AD pathology still being scanty [5].
Another possible marker of cognitive impairment in PD extensively used in recent years is the quantitative assessment of grey matter volume (GMV) with voxel-based morphometry (VBM) analysis of brain MRI [10]. A number of reports using this technique have suggested that limbic, paralimbic, and neocortical GMV reductions similar to those seen in AD may be the substrate of cognitive decline in PD [11].
In AD, CSF τ and Aβ markers have been shown to be associated with quantitative indicators of brain atrophy [12]. Since the relationship between these CSF and quantitative structural biomarkers in PD and PDD remains unaddressed, we aimed to study the associations of CSF τ, phospho-τ, and Aβ levels with GMV among the participants from our previous report having undergone high-field brain MRI, with the hypothesis that CSF markers of AD pathology might correlate with GMV in brain areas previously implicated in cognitive decline in PD.
Section snippets
Subjects and clinical protocol
We included 45 subjects from a sample already used in our previous studies [9], [13]: 33 PD patients (15 with dementia), along with 12 controls with normal neurological and neuropsychological examination and undergoing intradural anaesthesia for knee replacement surgery. These participants were the ones who underwent a high-field brain MRI around the time of the lumbar puncture, with the rest of subjects not having been eligible due to usual contraindications for MRI (pacemaker, certain type of
Demographic, clinical, neuropsychological and CSF data
These are summarised in Table 1 and are non-surprisingly consistent with those from the larger sample reported elsewhere [9] and from which the current one has been drawn. There were no significant differences in potential confounders as age or gender. All cases fulfilled the one year rule to distinguish DLB and PDD (shortest time to dementia in our cohort = 4 years; Supplementary Table 1). The highest CSF τ and, to lesser extent, phospho-τ levels concentrated in the PDD group, whereas CSF Aβ
Discussion
We report herein significant correlations between CSF markers of AD pathology and quantitative measures of brain atrophy in PDD in particular and across the PD cognitive continuum (PDND + PDD) in general.
We have discussed similar CSF data from a larger cohort elsewhere [9]. When applying tentative cut-offs, we have found abnormal levels in a greater proportion of cases for CSF Aβ than for CSF τ and phospho-τ, in keeping with the literature [5], [10], [11]. It is of note that CSF τ and phospho-τ
Acknowledgements
• To the patients, their families, and the control subjects, as without their support this study would not have been possible.
• We also acknowledge the invaluable help of Dr. M. Salazar, Dr. F. Basora, Dr. G. Sánchez-Etayo (Anesthesiology Service), Dr. F. Macule (Knee Surgery Unit), Mrs. A Martín, Mr. C. Garrido, and Mr. M. Fabregat (technicians from MRI unit of the Radiology Service), and to Dr. E. Gelpí (neuropathologist from our institution Brain Bank: Banc de Teixits Neurològics de
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